Browsing by Author "Saban, Daniel R."

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    CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes
    (Springer, 2016-11) Beli, Eleni; Dominguez, James M.; Hu, Ping; Thinschmidt, Jeffrey S.; Caballero, Sergio; Calzi, Sergio Li; Luo, Defang; Shanmugam, Sumathi; Salazar, Tatiana; Duan, Yaqian; Boulton, Michael E.; Mohr, Susanna; Abcouwer, Steven F.; Saban, Daniel R.; Harrison, Jeffrey K.; Grant, Maria B.; Ophthalmology, School of Medicine
    In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild type (WT), CX3CR1 null (CX3CR1gfp/gfp, KO) and heterozygous (CX3CR1+/gfp, Het) mice were compared in the presence and absence of streptozotocin (STZ) induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency and diabetes had similar effects on retinal neurodegeneration measured by an increase in DNA fragmentation. Retinal vascular pathology in STZ-KO mice was associated with increased numbers of monocyte-derived macrophages in the retina. Furthermore, compared to STZ-WT, STZ-KO mice exhibited increased numbers of inflammatory monocytes in the bone marrow and impaired homing of monocytes to the spleen. Induction of retinal IL-10 expression by diabetes was significantly less in KO mice, and when bone marrow-derived macrophages from KO mice were maintained in high glucose they expressed significantly less IL-10 and more TNF-α in response to LPS stimulation. These findings support that CX3CR1 deficiency accelerates the development of vascular pathology in DR through increased recruitment of proinflammatory myeloid cells that demonstrate reduced expression of anti-inflammatory IL-10.
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    The Mechanism of Diabetic Retinopathy Pathogenesis Unifying Key Lipid Regulators, Sirtuin 1 and Liver X Receptor
    (Elsevier, 2017-08) Hammer, Sandra S.; Beli, Eleni; Kady, Nermin; Wang, Qi; Wood, Kiana; Lydic, Todd A.; Malek, Goldis; Saban, Daniel R.; Wang, Xiaoxin X.; Hazra, Sugata; Levi, Moshe; Busik, Julia V.; Grant, Maria B.; Department of Ophthalmology, School of Medicine
    Diabetic retinopathy (DR) is a complication secondary to diabetes and is the number one cause of blindness among working age individuals worldwide. Despite recent therapeutic breakthroughs using pharmacotherapy, a cure for DR has yet to be realized. Several clinical trials have highlighted the vital role dyslipidemia plays in the progression of DR. Additionally, it has recently been shown that activation of Liver X receptor (LXRα/LXRβ) prevents DR in diabetic animal models. LXRs are nuclear receptors that play key roles in regulating cholesterol metabolism, fatty acid metabolism and inflammation. In this manuscript, we show insight into DR pathogenesis by demonstrating an innovative signaling axis that unifies key metabolic regulators, Sirtuin 1 and LXR, in modulating retinal cholesterol metabolism and inflammation in the diabetic retina. Expression of both regulators, Sirtuin 1 and LXR, are significantly decreased in diabetic human retinal samples and in a type 2 diabetic animal model. Additionally, activation of LXR restores reverse cholesterol transport, prevents inflammation, reduces pro-inflammatory macrophages activity and prevents the formation of diabetes-induced acellular capillaries. Taken together, the work presented in this manuscript highlights the important role lipid dysregulation plays in DR progression and offers a novel potential therapeutic target for the treatment of DR.